Compositions and Methods for Delivery of Poorly Soluble Drugs

ABSTRACT

Described herein are compositions comprising particles of poorly soluble drugs encapsulated by stabilizers. Further described are pharmaceutical compositions comprising such encapsulated compositions. Also described are methods of making such encapsulated particle compositions, and methods of making the corresponding pharmaceutical compositions. The encapsulated particle compositions described herein allow poorly soluble drugs to be administered with good bioavailability by routes that are non-invasive to patients, such as by oral administration.

This application claims priority to U.S. Provisional Application No.60/969,672, filed on Sep. 3, 2007, which is incorporated by reference inits entirety.

The U.S. Government has a paid-up license in this invention and theright in limited circumstances to require the patent owner to licenseothers on reasonable terms as provided for by the terms of Contract No.HHSN271200577414C awarded by the National Institute on Drug Abuse.

FIELD OF THE INVENTION

The present invention relates generally to compositions comprisingparticles of poorly soluble drugs encapsulated by stabilizers, and topharmaceutical compositions comprising such encapsulated compositions.It further relates to methods of making such encapsulated particlecompositions, and to methods of making the corresponding pharmaceuticalcompositions. The encapsulated particle compositions described hereinallow poorly soluble drugs to be administered with good bioavailabilityby routes that are non-invasive to patients, such as by oraladministration.

BACKGROUND

Oral administration of drugs is generally preferred for reasons ofpatient comfort and compliance. However, many drugs, including manyopioids, are poorly soluble at neutral pH, and are thus are poorly orvariably absorbed when delivered orally. Consequently, many such drugsare administered through more invasive routes, such as by sublingual,buccal, subcutaneous, or intravenous routes.

Several approaches for improving the oral delivery of poorly solubledrugs have demonstrated some promise. For example, poorly soluble drugshave been administered as dispersions in large amounts of fatty acids,and have been wet-milled to yield nanoparticles. However, each of thoseapproaches suffers from certain drawbacks, such as, e.g., inadequatestability, difficulty of manufacture, adverse interactions with the drugto be delivered, or the use of toxic amounts of adjuvants or inhibitors.Thus, there remains a need for compositions and methods for thenon-invasive delivery of poorly soluble drugs.

SUMMARY

In some embodiments, the invention provides a composition comprisingparticles of a poorly soluble drug (such as, e.g., an opioid)encapsulated by a stabilizer. The stabilizer may be, e.g., a polymer,including, e.g., a water-soluble polymer of neutral charge. For example,in some embodiments, the invention provides a composition comprisingparticles of buprenorphine encapsulated by PEG, wherein thebuprenorphine content ranges from about 0.2% to about 4%. In otherembodiments, the composition further comprises a surfactant, such as,e.g., a polysorbate surfactant.

In other embodiments, the invention provides pharmaceutical compositionscomprising such encapsulated compositions. Such pharmaceuticalcompositions may, in some embodiments, further comprise at least oneexcipient. In other embodiments, such pharmaceutical compositions mayfurther comprise a second compound such as, e.g., a second drug,including, e.g., an opioid receptor antagonist, an anti-inflammatorydrug, or an analgesic. For example, in some embodiments, the inventionprovides a pharmaceutical composition comprising a compositioncomprising the PEG-encapsulated buprenorphine composition describedabove. In certain embodiments, the pharmaceutical composition furthercomprises naloxone.

In some embodiments, the invention provides a first method of making acomposition comprising particles of a poorly soluble drug encapsulatedby a stabilizer, the method comprising:

-   -   blending a poorly soluble drug together with a stabilizer to        form a mixture;    -   processing said mixture to form coarse particles having an        average diameter ranging from about 0.1 mm to about 5 mm; and    -   processing said coarse particles to form fine particles having        an average diameter ranging from about 0.1 mm to about 3 mm.

In some embodiments, the invention provides a second method of making acomposition comprising particles of a poorly soluble drug encapsulatedby a stabilizer, the method comprising:

-   -   blending a poorly soluble drug together with a stabilizer to        form a mixture;    -   heating said mixture to a temperature sufficient for extrusion        of the mixture;    -   extruding said mixture to form coarse particles having an        average diameter ranging from about 0.1 mm to about 5 mm;    -   cooling said coarse particles; and    -   processing said coarse particles to form fine particles having        an average diameter ranging from about 0.1 mm to about 3 mm.

In further embodiments, the invention provides a method of making apharmaceutical composition, comprising the first or second methoddescribed above, and further comprising:

-   -   formulating the fine particles.

In further embodiments, the invention provides a method of making apharmaceutical composition, comprising the first or second methoddescribed above, and further comprising:

-   -   mixing the fine particles with at least one excipient to form a        second mixture; and    -   formulating the second mixture.

In yet other embodiments, the invention provides a method of treatingpain, comprising administering the pharmaceutical composition describedabove to a patient in need thereof. In other embodiments, the inventionprovides a method of treating opiate addiction, comprising administeringthe pharmaceutical composition described above to a patient in needthereof.

DETAILED DESCRIPTION I. Particulate Delivery Systems

In some embodiments, the invention provides a composition (also referredto as a particulate delivery system or PDS) comprising particles of apoorly soluble drug encapsulated by a stabilizer. In some embodiments,those particles are fine particles, and have a diameter of less than 3mm, less than 2 mm, less than 600 μm, less than 500 μmm, or less than300 μm. In some embodiments, the fine particles have an average diameterranging from about 0.1 mm (100 μm) to about 3 mm. For example, theparticles may have a diameter of less than 2.06 mm (corresponding to a10 mesh sieve), less than 1.68 mm (corresponding to a 12 mesh sieve),less than 1.40 mm (corresponding to a 14 mesh sieve), less than 1.20 mm(corresponding to a 16 mesh sieve), less than 1.00 mm (corresponding toan 18 mesh sieve), less than 0.853 mm (corresponding to a 20 meshsieve), less than 0.710 mm (corresponding to a 25 mesh sieve), less than0.599 mm (corresponding to a 30 mesh sieve), or less than 0.500 mm(corresponding to a 35 mesh sieve). In other embodiments, the particlesmay have a diameter of less than 300 μm, and may be able to pass througha 50 mesh sieve.

As used herein, the term drug encompasses the corresponding salts,hydrates, solvates, prodrugs, and complexes of the drug. Thus, the drugmay be present as, e.g., a free base, a salt, a hydrate, a prodrug, asolvate (including a mixed solvate), or a complex (such as apharmaceutically acceptable complex, and/or a complex with a polymer).

As used herein, the terms poorly soluble drug, drug having poorsolubility, and the like refer to a drug (in its neutral (i.e.,uncharged) state) having a water solubility at neutral pH of less than10 mg/ml. In some embodiments, the drug (in its neutral state) has awater solubility at neutral pH of less than 5 mg/mi. In otherembodiments, the drug (in its neutral state) has a water solubility atneutral pH of less than 1 mg/ml. For example, buprenorphine base (i.e.,uncharged buprenorphine) has a solubility at neutral pH of <1 mg/ml(whereas the corresponding hydrochloride salt has a solubility atneutral pH of 17 mg/ml). Thus, as used herein, buprenorphine (includingbuprenorphine base and its salts, hydrates, solvates, complexes, etc.)is a poorly soluble drug. Similarly, morphine base (i.e., unchargedmorphine) has a solubility at neutral pH of <1 mg/ml (whereas thecorresponding sulfate has a solubility at neutral pH of 64 mg/ml). Thus,as used herein, morphine (including morphine base and its salts,hydrates, solvates, complexes, etc.) is a poorly soluble drug. In athird example, oxycodone base (i.e., uncharged oxycodone) has asolubility at neutral pH of <1 mg/ml (whereas the correspondinghydrochloride has a solubility at neutral pH of 100 mg/ml). Thus, asused herein, oxycodone (including oxycodone base and its salts,hydrates, solvates, complexes, etc.) is a poorly soluble drug.

In certain embodiments, the poorly soluble drug is chosen from opioids(including opiates). Opioids include naturally-occurring, synthetic, andsemi-synthetic opioids, such as, e.g., alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonidine, clonitazene, codeine, cyclazocine, desomorphine,dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazine, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levallorphan, levomethadyl, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, naloxone, naltrexone, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, remifentanil, sulfentanil, tramadol, and tilidine. Forexample, in some embodiments, the opioid may be chosen from, e.g.,buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, morphine,methylnaltrexone, nalbuphine, nalmefene, oxymorphone, oxycodone,pethidine, and tramadol.

In some embodiments, the PDS may further comprise an additionalcompound, such as an additional drug. The additional drug may be chosenfrom, e.g., opioid receptor antagonists (including μ-receptorantagonists), opioid receptor agonists (including μ-receptor agonists),mixed μ-agonists/μ-antagonists, anti-inflammatory drugs, and analgesics.In some embodiments, the second drug is an opioid receptor antagonist,such as, e.g., the μ-opioid receptor antagonist naloxone, includingnaloxone.HCl (naloxone hydrochloride). In some embodiments where thepoorly soluble drug is an opioid analgesic, the opioid receptorantagonist is added to deter abuse of the opioid analgesic.

The poorly soluble drug may be present in an amount ranging from about<1% to about 90% of the PDS by mass. For example, the poorly solubledrug may be present in an amount ranging from about 0.01% to about 90%,about 0.01% to about 10%, about 0.2 to about 5%, about <1% to about 10%,about 0.01% to about 10%, about 0.1% to about 10%, about 0.01% to about5%, about 0.1% to about 5%, about 0.1% to about 3%, about <1% to about50%, about <1% to about 30%, about <1% to about 80%, about 5% to about90%, about 10% to about 95%, or about 0.1 to about 5% of the PDS, bymass. In some embodiments, the poorly soluble drug content may be about0.5% by mass.

In some embodiments, the stabilizer is a polymer, such as, e.g., awater-soluble polymer, a polymer of neutral charge, or a water-solublepolymer of neutral charge. In some embodiments, the stabilizer isbiodegradable. In some embodiments, the stabilizer is bioerodable. Insome embodiments, the stabilizer may be considered by the FDA to begenerally regarded as safe (GRAS).

In some embodiments, the stabilizer is a polymer chosen frompolyethylene oxide (also known as polyethylene glycol or PEG),polypropylene oxide, or copolymers thereof. In some embodiments, thestabilizer is a water-soluble polymer of neutral charge chosen frompolyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (PVP),block copolymers of ethylene oxide and propylene oxide such as, e.g.,poloxamers, and tetrafunctional block copolymers derived from sequentialaddition of propylene oxide and ethylene oxide to ethylenediamine.

In some embodiments, the stabilizer may have an average molecular weightof about, e.g., 500, 1000, 2000, 3000, 3350, 3500, 4000, 4500, 5000,6000, 8000, 10,000, or 100,000 Da, or an average molecular weightranging from, e.g., about 100 Da to about 100,000 Da, about 100 Da toabout 6,000 Da, about 500 Da to about 5000 Da, about 1000 Da to about4000 Da, about 2000 Da to about 4000 Da, about 2000 Da to about 6000 Da,about 1000 Da to about 10,000 Da, or about 3000 Da to about 4000 Da.

For example, the stabilizer may be a PEG, such as a PEG of averagemolecular weight of about, e.g., 500, 1000, 2000, 3000, 3350, 3500,4000, 4500, 5000, 6000, 8000, 10,000 or 100,000 Daltons. In exemplaryembodiments, the stabilizer is PEG having an average molecular weight of3350 Daltons (i.e., PEG 3350). In other embodiments, the stabilizer maybe a PEG having an average molecular weight ranging from, e.g., about100 Da to about 100,000 Da, about 100 Da to about 6,000 Da, about 500 Dato about 5000 Da, about 1000 Da to about 4000 Da, about 2000 Da to about4000 Da, about 2000 Da to about 6000 Da, about 1000 Da to about 10,000Da, or about 3000 Da to about 4000 Da.

In some embodiments, the composition further comprises at least oneexcipient, such as, e.g., a surfactant, surface stabilizer, or otherenhancer. For example, in some embodiments, the composition furthercomprises at least one surfactant, which may be a nonionic surfactantsuch as, e.g., a polysorbate surfactant. In exemplary embodiments, thecomposition further comprises polysorbate 20 (Tween 20). In otherembodiments, the composition further comprises an emulsifier, such as,e.g., a phospholipid, propylene glycol, polysorbate, poloxamer, glycerylmonostearate, or other pharmaceutical emulsifier.

In certain embodiments, the composition comprises an opioid, a PEG, anda surfactant. In some embodiments, the invention provides a compositioncomprising particles of buprenorphine (such as, e.g., buprenorphine.HCl)encapsulated by PEG (which, in some embodiments, may have an averagemolecular weight ranging from about 500 Daltons to about 10,000Daltons), wherein the buprenorphine content ranges from about 0.2% toabout 4%. In further embodiments, the particles have an average diameterof less than 2 mm. In some embodiments, the composition furthercomprises a surfactant. In certain embodiments, the PDS comprisesbuprenorphine, PEG 3350, and Tween 20.

II. Methods of Making PDS

In some embodiments, the invention provides a first method of making acomposition (such as those described in Section I) comprising particlesof a poorly soluble drug encapsulated by a stabilizer, the methodcomprising:

-   -   blending a poorly soluble drug together with a stabilizer to        form a mixture;    -   processing (e.g., by mixing or granulating) said mixture to form        coarse particles having an average diameter ranging from about        0.1 mm to about 5 mm; and    -   processing (e.g., by milling, grinding, or crushing) said coarse        particles to form fine particles having an average diameter        ranging from about 0.1 mm to about 3 mm.

In certain embodiments, the fine particles have an average diameterranging from about 0.1 mm (100 μm) to about 3 mm. For example, theparticles may have a diameter of less than 2.06 mm (corresponding to a10 mesh sieve), less than 1.68 mm (corresponding to a 12 mesh sieve),less than 1.40 mm (corresponding to a 14 mesh sieve), less than 1.20 mm(corresponding to a 16 mesh sieve), less than 1.00 mm (corresponding toan 18 mesh sieve), less than 0.853 mm (corresponding to a 20 meshsieve), less than 0.710 mm (corresponding to a 25 mesh sieve), less than0.599 mm (corresponding to a 30 mesh sieve), or less than 0.500 mm(corresponding to a 35 mesh sieve). In other embodiments, the particlesmay have a diameter of less than 300 μm, and may be able to pass througha 50 mesh sieve. In certain embodiments, the particles have a diameterof 0.6 mm or less.

In certain embodiments, the stabilizer is heated prior to blending withthe poorly soluble drug.

In other embodiments, the invention provides a second method of making acomposition (such as those described in Section I) comprising particlesof a poorly soluble drug encapsulated by a stabilizer. The second methoduses a relatively continuous manufacturing process, which may beadvantageous in certain circumstances. The second method comprises:

-   -   blending a poorly soluble drug together with a stabilizer to        form a mixture;    -   heating said mixture to a temperature sufficient for extrusion        of the mixture;    -   extruding said mixture to form coarse particles having an        average diameter ranging from about 0.1 mm to about 5 mm;    -   cooling said coarse particles; and    -   processing (e.g., by milling, grinding, or crushing) said coarse        particles to form fine particles having an average diameter        ranging from about 0.1 mm to about 3 mm.

In certain embodiments, the fine particles have an average diameterranging from about 0.1 mm (100 m) to about 3 mm. For example, theparticles may have a diameter of less than 2.06 mm (corresponding to a10 mesh sieve), less than 1.68 mm (corresponding to a 12 mesh sieve),less than 1.40 mm (corresponding to a 14 mesh sieve), less than 1.20 mm(corresponding to a 16 mesh sieve), less than 1.00 mm (corresponding toan 18 mesh sieve), less than 0.853 mm (corresponding to a 20 meshsieve), less than 0.710 mm (corresponding to a 25 mesh sieve), less than0.599 mm (corresponding to a 30 mesh sieve), or less than 0.500 mm(corresponding to a 35 mesh sieve). In other embodiments, the particlesmay have a diameter of less than 300 μm, and may be able to pass througha 50 mesh sieve. In certain embodiments, the particles have a diameterof 0.6 mm or less.

In certain embodiments, the stabilizer is heated prior to blending withthe poorly soluble drug.

III. Pharmaceutical Compositions (Final Dosage Forms)

In some embodiments, the invention provides pharmaceutical compositions(sometimes referred to as final dosage forms or FDF) comprising thecompositions described in Section I above.

The poorly soluble drug may be present in the pharmaceutical compositionin an amount ranging from about <1% to about 90% by mass. For example,the poorly soluble drug may be present in an amount ranging from about0.01% to about 90%, about 0.01% to about 10%, about 0.2 to about 5%,about <1% to about 10%, about 0.01% to about 10%, about 0.1% to about10%, about 0.01% to about 5%, about 0.1% to about 5%, about 0.1% toabout 3%, about <1% to about 50%, about <1% to about 30%, about <1% toabout 80%, about 5% to about 90%, about 10% to about 95%, or about 0.1to about 5% of the pharmaceutical composition by mass. In someembodiments, the poorly soluble drug content may be about 0.5% by mass.

In some embodiments, the pharmaceutical compositions further comprise asecond compound, such as a second drug. The second drug may be chosenfrom, e.g., opioid receptor antagonists (including μ-receptorantagonists), opioid receptor agonists (including μ-receptor agonists),mixed μ-agonists/μ-antagonists, anti-inflammatory drugs, and analgesics.In some embodiments, the second drug is an opioid receptor antagonist,such as, e.g., the μ-opioid receptor antagonist naloxone, includingnaloxone.HCl (naloxone hydrochloride). In some embodiments where thepoorly soluble drug is an opioid analgesic, the opioid receptorantagonist is added to deter abuse of the opioid analgesic. Theresulting compositions may have reduced potential for abuse of theopioid, relative to compositions that do not comprise an opioid receptorantagonist.

In some embodiments, the pharmaceutical compositions further comprise atleast one excipient (such as, e.g., a water-soluble polymer, surfactant,and/or enhancer), such as a pharmaceutically acceptable excipient.Examples of pharmaceutically acceptable excipients are described inRemington's Pharmaceutical Sciences by E. W. Martin, and include starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol, and thelike. In some embodiments, the pharmaceutical compositions also containpH buffering reagents, and wetting or emulsifying agents.

The pharmaceutical compositions may, in some embodiments, be formulatedfor oral administration, for example as tablets, capsules, or other oraldosage forms. Such oral dosage forms may be prepared by conventionalmeans. The pharmaceutical composition can also be prepared as a liquid,for example as a syrup or a suspension. The liquid can includesuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats), emulsifying agents (lecithin or acacia),non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, orfractionated vegetable oils), and preservatives (e.g., methyl orpropyl-p-hydroxybenzoates or sorbic acid). The preparations can alsoinclude flavoring, coloring and sweetening agents. Alternatively, thecomposition can be presented as a dry product for constitution withwater or another suitable vehicle.

For buccal and sublingual administration, the composition may take theform of tablets or lozenges according to conventional protocols.

For administration by oral inhalation, the compounds for use accordingto the present invention are conveniently delivered in the form of anaerosol spray from a pressurized pack or nebulizer (e.g., in PBS), witha suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitcan be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator can be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The pharmaceutical composition can also be formulated for parenteraladministration (including, e.g., intravenous or intramuscularadministration) by bolus injection. Formulations for injection can bepresented in unit dosage form, e.g., in ampoules or in multidosecontainers with an added preservative. The compositions can take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and contain formulatory agents such as suspending, stabilizingand/or dispersing agents. Alternatively, the active ingredient can be inpowder form for constitution with a suitable vehicle, such as, e.g.,pyrogen free water.

The pharmaceutical composition can also be formulated for rectaladministration as a suppository or retention enema, e.g., containingconventional suppository bases such as PEG, cocoa butter or otherglycerides.

In some embodiments, the pharmaceutical compositions described hereinprovide improved dissolution of the poorly soluble drug, relative to theunencapsulated poorly soluble drug, and/or to another dosage form (suchas, e.g., a more invasive dosage form). For example, dissolution may beincreased by, e.g., at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%,60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%,130%, 140%, 150%, or 200%, or by, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9,10, 20, 30, 40, 50, 100, or 1000 fold, as measured by a Vankel tabletdissolution apparatus approved by the United States Pharmacopeia.

In some embodiments, the pharmaceutical compositions described hereinprovide improved oral bioavailability of the poorly soluble drug,relative to the unencapsulated poorly soluble drug, and/or to anotherdosage form (such as, e.g., a more invasive dosage form). For example,absorption may be increased by, e.g., at least 10%, 15%, 20%, 25%, 30%,35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, 100%,110%, 120%, 130%, 140%, 150%, or 200%, or by, e.g., at least 2, 3, 4, 5,6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or 1000 fold, as measured by, e.g.,in vivo pharmacokinetic studies in a preclinical animal model or humanclinical evaluation.

In some embodiments, the pharmaceutical compositions described hereinare immediate-release formulations. In such embodiments, thepharmaceutical compositions provide a more rapid onset of action of thepoorly soluble drug, relative to the unencapsulated poorly soluble drug,and/or to another dosage form (such as, e.g., a more invasive dosageform). For example, the onset of action may be shortened by, e.g., atleast 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%,95%, 96%, 97%, 98%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, or 200%, orby, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or1000 fold, as measured by, e.g., in vivo pharmacokinetic studies in apreclinical animal model or human clinical evaluation.

In other embodiments, the pharmaceutical compositions described hereinare controlled-release formulations. In such embodiments, thepharmaceutical compositions described herein provide a more rapid onsetof action of the poorly soluble drug.

In some embodiments, the pharmaceutical compositions described hereinhave reduced absorption variability, relative to the unencapsulatedpoorly soluble drug, and/or to another dosage form (such as, e.g., amore invasive dosage form).

In some embodiments, the pharmaceutical compositions described hereinare associated with improved patient compliance, relative to anotherpharmaceutical composition comprising the same poorly soluble drug(which may be in another dosage form, such as, e.g., a more invasivedosage form).

IV. Methods of Making Pharmaceutical Compositions

In further embodiments, the invention provides a method of making apharmaceutical composition, comprising the first, second, or thirdmethod described in Section II above, and further comprising:

-   -   formulating the fine particles.

In certain embodiments, the fine particles are formulated into unitdoses.

In embodiments in which the pharmaceutical compositions comprise atleast one excipient, the invention also provides a method of making apharmaceutical composition, comprising the first, second, or thirdmethod described in Section II above, and further comprising:

-   -   mixing the fine particles with at least one excipient to form a        second mixture; and    -   formulating the second mixture.

In certain embodiments, the fine particles are formulated into unitdoses.

V. Methods of Treatment

The pharmaceutical compositions described herein are useful to treat anydisease or condition for which administration of a correspondinghydrophobic drug is desirable. For example, compositions comprisingopioids are useful for the treatment of pain. The terms “treat,”treatment,” and “treating” refer to (1) a reduction in severity orduration of a disease or condition, (2) the amelioration of one or moresymptoms associated with a disease or condition without necessarilycuring the disease or condition, or (3) the prevention of a disease orcondition. Suitable subjects include, e.g., humans and other mammals,such as, e.g., mice, rats, dogs, and non-human primates.

In certain embodiments, the invention provides a method of treatingpain, comprising administering a pharmaceutical composition described inSection III to a subject in need thereof. For example, in suchembodiments, the poorly soluble drug may be chosen from, e.g., opioids,including, e.g., buprenorphine, codeine, fentanyl, hydrocodone,hydromorphone, morphine, methylnaltrexone, nalbuphine, nalmefene,oxymorphone, oxycodone, pethidine, and tramadol. Moreover, in suchembodiments, the pharmaceutical composition may further comprise anopioid receptor antagonist, such as, e.g., naloxone or naltrexone, todeter abuse of the opioid analgesic.

In other embodiments, the invention provides a method of treating opiateaddiction, comprising administering a pharmaceutical compositiondescribed in Section III to a subject in need thereof. For example, insuch embodiments, the poorly soluble drug may be chosen from, e.g.,methadone, naloxone, and naltrexone.

The following examples are intended to be purely exemplary of thepresent invention.

Examples Example 1: Preparation of Buprenorphine.HCl PDS

A solution of 1 kg of autoclaved polyethylene glycol (Dow, PEG 3350, NF,FCC) and polysorbate (Tween 20, FCC), at a 10:1 mass ratio, cooled toless then 60° C., is aseptically mixed with 20 g of buprenorphine.HCl(Johnson Matthey, milled USP grade) powder. The suspension (whichcontains 2% buprenorphine) is then blended in a paddle mixer and furtheragitated using low-frequency sonication (as described in U.S. Pat. Appl.Pub. No. 2005/0175707) to form buprenorphine.HCl particles encapsulatedin a PEG/Tween matrix. The powder is then frozen at −20° C. for at least2 hours and then ground into a fine powder using a Retsch knife mill.Particles smaller than 600 m are separated by sieving (30 mesh).Buprenorphine content is confirmed using an HPLC method.

Example 2: Preparation of Immediate-Release Oral Buprenorphine.HClCapsules

An immediate-release oral dosage form (gelatin capsules) containing thebuprenorphine.HCl particles prepared in Example 1, as well asnaloxone.HCl as an abuse-deterrent second drug, is prepared as describedbelow. The PDS prepared in Example 1 is dry mixed with naloxone (asnaloxone.HCl dihydrate, USP) and additional PEG 3350 for bulking toachieve the correct capsule fill weight (400-500 mg) to achieve thedesired dose. Clear gelatin #1 capsules are then filled with the mixturein a Fast-CAP Filling machine to yield capsules containing 2.0±0.2 mgbuprenorphine (with respect to the free base) and 0.5±0.05 mg naloxone(with respect to the free base). The capsules thus contain buprenorphineand naloxone at a ratio of 4:1, with respect to the free bases.

Example 3: Dissolution of Immediate-Release Oral Buprenorphine.HClCapsules

The in vivo dissolution rate of the fast-release formulation prepared inExample 2 was measured by USP Paddle Method 2 at 50 or 100 rpm in 900 mlof 0.1 N HCl acidic buffer (pH between 1.6 and 3) at 37° C. It was foundthat greater then 75% (by weight) of the therapeutically active agentwas released after 45 minutes.

Example 4: Single-Dose Pharmacokinetic Study in Rats

The composition prepared in Example 2 (prior to loading into gelatincapsules) was administered via oral gavage once daily for 14 consecutivedays to male and female F-344 rats at a low (0.03 mg/kg) or high (0.5mg/kg) dose (n=10 each). Plasma samples collected up to 8 hours fromsingle-dose pharmacokinetic (PK) studies in male rats (non-GLP) werecompared to 14-day samples using a validated extraction and LC-MS-MSanalytical method.

Values for the single-dose PK study were 0.53 and 4.07 ng/ml for malerats administered 0.03 and 0.5 mg/kg, respectively (n=3-5), observed atthe first 15 minute collection time. The concentration-time profilesdeclined from C_(max) in mono- or multi-exponential relationships. AUCvalues for the single-dose PK study were 2.51 and 10.33 ng-hr/ml formale rats administered 0.03 and 0.5 mg/kg, respectively (n=3-5). At day14 of the repeat dose toxicity study for rats administered 0.03 and 0.5mg/kg, respectively (n=4 each), C_(max) values were 1.57 and 4.11 ng/mlfor males and 1.85 and 4.12 ng/ml for females, also observed at the 30minute collection time. C_(max) values were similar for males andfemales based on 30 minute and 8 hour time points from 14-day plasmasamples analyzed. Norbuprenorphine, the main metabolite ofbuprenorphine, and naloxone plasma concentrations were below the limitof quantitation.

Example 5: Preparation of Pharmaceutical Compositions ComprisingOxycodone

Pharmaceutical compositions comprising oxycodone may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Oxycodone content   0.1-200 mg PEG 1500 content 100-1000 mg

Example 6: Preparation of Controlled-Release Pharmaceutical CompositionsComprising Oxycodone

Controlled-release pharmaceutical compositions comprising oxycodone maybe prepared according to the methods of the invention. The compositionsmay have the following characteristics:

Oxycodone content   0.1-200 mg PVP K-30 content 100-1000 mg

Example 7: Preparation of Pharmaceutical Compositions ComprisingMorphine

Pharmaceutical compositions comprising morphine may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Morphine content   0.1-100 mg Poloxamer 407 content 100-1000 mg

Example 8: Preparation of Controlled-Release Pharmaceutical CompositionsComprising Morphine

Controlled-release pharmaceutical compositions comprising morphine maybe prepared according to the methods of the invention. The compositionsmay have the following characteristics:

Morphine content   0.1-100 mg PEG 8000 content 100-1000 mg

Example 9: Preparation of Pharmaceutical Compositions ComprisingHydrocodone

Pharmaceutical compositions comprising hydrocodone may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Hydrocodone content   0.1-100 mg PEG 3350 content 100-1000 mg

Example 10: Preparation of Pharmaceutical Compositions ComprisingDihydrocodone

Pharmaceutical compositions comprising dihydrocodone may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Dihydrocodone content   0.1-100 mg PEG 3350 content 100-1000 mg

Example 11: Preparation of Pharmaceutical Compositions ComprisingCodeine

Pharmaceutical compositions comprising codeine may be prepared accordingto the methods of the invention. The compositions may have the followingcharacteristics:

Codeine content   0.1-100 mg Poloxamer 407 content 100-1000 mg

Example 12: Preparation of Pharmaceutical Compositions ComprisingMeperidine

Pharmaceutical compositions comprising meperidine may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Meperidine content   0.1-500 mg PEG 3350 content 100-1000 mg

Example 13: Preparation of Pharmaceutical Compositions ComprisingPropoxyphene

Pharmaceutical compositions comprising propoxyphene may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Propoxyphene content   0.1-500 mg PEG 3350 content 100-1000 mg

Example 14: Preparation of Pharmaceutical Compositions ComprisingLevorphanol

Pharmaceutical compositions comprising levorpanol may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Levorphanol content   0.1-100 mg Poloxamer 407 content 100-1000 mg

Example 15: Preparation of Pharmaceutical Compositions ComprisingOxymorphone

Pharmaceutical compositions comprising oxymorphone may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Oxymorphone content   0.1-200 mg PEG 3350 content 100-1000 mg

Example 16: Preparation of Pharmaceutical Compositions ComprisingHydromorphone

Pharmaceutical compositions comprising hydromorphone may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Hydromorphone content   0.1-100 mg Poloxamer 407 content 100-1000 mg

Example 17: Preparation of Pharmaceutical Compositions ComprisingFentanyl

Pharmaceutical compositions comprising hydromorphone may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Fentanyl content   0.1-500 mg PEG 3350 content 100-1000 mg

Example 18: Preparation of Pharmaceutical Compositions ComprisingAlfentanyl

Pharmaceutical compositions comprising alfentanyl may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Alfentanyl content 0.01-50 μg PEG 3350 content 100-1000 mg

Example 19: Preparation of Pharmaceutical Compositions ComprisingSufentanyl

Pharmaceutical compositions comprising sulfentanyl may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Sulfentanyl content 0.01-500 μg PEG 3350 content 100-1000 mg

Example 20: Preparation of Pharmaceutical Compositions ComprisingRemifentanyl

Pharmaceutical compositions comprising remifentanyl may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Remifentanyl content 0.01-500 μg PEG 3350 content 100-1000 mg

Example 21: Preparation of Pharmaceutical Compositions ComprisingLevomethadyl

Pharmaceutical compositions comprising levomethadyl may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Levomethadyl content 0.01-200 mg Poloxamer 407 content 100-1000 mg

Example 22: Preparation of Pharmaceutical Compositions ComprisingMethadone

Pharmaceutical compositions comprising methadone may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Methadone content  0.01-200 mg PEG 3350 content 100-1000 mg

Example 23: Preparation of Pharmaceutical Compositions ComprisingButorphanol

Pharmaceutical compositions comprising butorphanol may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Butorphanol content   0.1-200 mg PEG 3350 content 100-1000 mg

Example 24: Preparation of Pharmaceutical Compositions ComprisingDezocine

Pharmaceutical compositions comprising dezocine may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Dezocine content   0.1-200 mg Poloxamer 407 content 100-1000 mg

Example 25: Preparation of Pharmaceutical Compositions ComprisingNalbuphine

Pharmaceutical compositions comprising nalbuphine may be preparedaccording to the methods of the invention. The compositions may have thefollowing characteristics:

Nalbuphine content   0.1-200 mg PEG 3350 content 100-1000 mg

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with the true scope and spiritof the invention being indicated by the following claims.

1. A composition comprising particles of a poorly soluble drugencapsulated by a stabilizer.
 2. The composition of claim 1, wherein theparticles have an average diameter of less than 2 mm.
 3. The compositionof claim 2, wherein the particles have an average diameter of less than500 μm.
 4. The composition of claim 3, wherein the particles have anaverage diameter of less than 300 μm.
 5. The composition of claim 1,wherein the poorly soluble drug is an opioid.
 6. The composition ofclaim 5, wherein the opioid is chosen from buprenorphine, codeine,fentanyl, hydrocodone, hydromorphone, morphine, methylnaltrexone,nalbuphine, nalmefene, oxymorphone, oxycodone, pethidine, and tramadol.7. The composition of claim 6, wherein the opioid is buprenorphine. 8.The composition of claim 7, wherein the buprenorphine is a buprenorphinesalt.
 9. The composition of claim 8, wherein the buprenorphine salt isbuprenorphine.HCl.
 10. The composition of claim 1, wherein thestabilizer is a polymer.
 11. The composition of claim 10, wherein thestabilizer is a water-soluble polymer.
 12. The composition of claim 10,wherein the stabilizer is a polymer of neutral charge.
 13. Thecomposition of claim 10, wherein the stabilizer is a water-solublepolymer of neutral charge.
 14. The composition of claim 13, wherein thewater-soluble polymer of neutral charge is chosen from polyethyleneglycol (PEG), polyvinyl alcohol, polyvinylpyrrolidone, block copolymersof ethylene oxide and propylene oxide, and tetrafunctional blockcopolymers derived from sequential addition of propylene oxide andethylene oxide to ethylenediamine.
 15. The composition of claim 14,wherein the polymer is PEG.
 16. The composition of claim 15, wherein thePEG has an average molecular weight ranging from about 100 Daltons toabout 100,000 Daltons.
 17. The composition of claim 16, wherein the PEGis PEG
 3350. 18. The composition of claim 1, wherein the poorly solubledrug is present in an amount ranging from about 0.01% to about 90% bymass.
 19. The composition of claim 18, wherein the poorly soluble drugis present in an amount ranging from about 0.01% to about 10% by mass.20. The composition of claim 19, wherein the poorly soluble drug ispresent in an amount ranging from about 0.2% to about 5% by mass. 21.The composition of claim 20, wherein the poorly soluble drug content isabout 0.5% by mass.
 22. The composition of claim 1, further comprisingat least one excipient.
 23. The composition of claim 22, wherein the atleast one excipient is a surfactant.
 24. The composition of claim 23,wherein the surfactant is a nonionic surfactant.
 25. The composition ofclaim 24, wherein the nonionic surfactant is a polysorbate surfactant.26. The composition of claim 25, wherein the polysorbate surfactant isTween
 20. 27. A pharmaceutical composition comprising the composition ofclaim
 1. 28. The pharmaceutical composition of claim 27, furthercomprising a second compound.
 29. The pharmaceutical composition ofclaim 28, wherein the second compound is a second drug.
 30. Thepharmaceutical composition of claim 29, wherein the second drug ischosen from opioid receptor antagonists, anti-inflammatory drugs, andanalgesics.
 31. The pharmaceutical composition of claim 30, wherein thesecond drug is an opioid receptor antagonist.
 32. The pharmaceuticalcomposition of claim 31, wherein the second drug is naloxone.
 33. Thepharmaceutical composition of claim 32, wherein the naloxone is analoxone salt.
 34. The pharmaceutical composition of claim 33, whereinthe naloxone salt is naloxone.HCl.
 35. The pharmaceutical composition ofclaim 27, wherein the pharmaceutical composition further comprises atleast one excipient.
 36. The pharmaceutical composition of claim 35,wherein the at least one excipient is chosen from polyethylene glycol(PEG), polyvinyl alcohol, polyvinylpyrrolidone, block copolymers ofethylene oxide and propylene oxide, and tetrafunctional block copolymersderived from sequential addition of propylene oxide and ethylene oxideto ethylenediamine.
 37. A pharmaceutical composition according to claim27, wherein the pharmaceutical composition is formulated for oraladministration.
 38. A method of making the composition of claim 1, themethod comprising: blending an opioid together with a stabilizer to forma mixture; processing said mixture to form coarse particles having anaverage diameter ranging from about 0.1 mm to about 5 mm; and processingsaid coarse particles to form fine particles having an average diameterranging from about 0.1 mm to about 3 mm.
 39. A method of making thecomposition of claim 1, the method comprising: blending an opioidtogether with a stabilizer to form a mixture; heating said mixture to atemperature sufficient for extrusion of the mixture; extruding saidmixture to form coarse particles having an average diameter ranging fromabout 0.1 mm to about 5 mm; cooling said coarse particles; andprocessing said coarse particles to form fine particles having anaverage diameter ranging from about 0.1 mm to about 3 mm.
 40. A methodof making a pharmaceutical composition, comprising the method of claim38, and further comprising: formulating the fine particles.
 41. A methodof making a pharmaceutical composition, comprising the method of claim39, and further comprising: formulating the fine particles.
 42. A methodof treating pain, comprising administering the pharmaceuticalcomposition of claim 27 to a patient in need thereof.
 43. The method ofclaim 42, wherein the poorly soluble drug is an opioid.
 44. A method oftreating opiate addiction, comprising administering the pharmaceuticalcomposition of claim 27 to a patient in need thereof.
 45. The method ofclaim 44, wherein the poorly soluble drug is chosen from methadone,naloxone, and naltrexone.
 46. A composition comprising particles ofbuprenorphine encapsulated by PEG, wherein the buprenorphine contentranges from about 0.2% to about 4%.
 47. The composition of claim 46,wherein the particles have an average diameter of less than 2 mm. 48.The composition of claim 47, wherein the buprenorphine isbuprenorphine.HCl.
 49. The composition of claim 46, wherein the PEG hasan average molecular weight ranging from about 500 Daltons to about10,000 Daltons.
 50. The composition of claim 49, wherein the PEG is PEG3350.
 51. The composition of claim 46, further comprising a surfactant.52. A pharmaceutical composition comprising the composition of claim 46and naloxone.
 53. The pharmaceutical composition of claim 52, whereinthe composition is formulated for oral administration.